Abstract: Tantalizing advances in stem cell biology have led to the promise of incredible new therapeutic options for an array of illnesses. Yet, the reality is that continued obstacles have thus far delayed the translation of most these potential advances in regenerative medicine into the clinic where they can be used for patients. This is in part because of missing tools that control how and when stem cells commit to a lineage (stem cell fate) and differentiate. Glucocorticoids such as cortisol, the natural hormone, or a multitude of synthetic cortisol analogues used as drugs, are heavily relied upon in stem cell biology because of their potent ability to induce cell fate decisions and differentiation of precursor cells. For example, glucocorticoids play a critical role in the induction of adipocyte cell fate and differentiation both in vivo and ex vivo. In fact, glucocorticoids have been indispensable for the progress made in understanding down-stream events of stem cell differentiation. Yet, the mechanisms by which glucocorticoids initiate cell fate decisions is mostly unexplored. Here I propose a novel paradigm where the circadian clock, controlling 24-hour body rhythms, is embedded in the glucocorticoid pathway and is essential for the regulation of stem cell fate. To test my hypothesis, I will develop innovative, interdisciplinary tools to reveal the molecular connections between stem cells, nuclear hormone receptors and circadian rhythm biology. The new knowledge to be gained from these studies will likely allow the design of drugs to direct selective precursor cells down a desirable and healthful lineage of differentiation and away from a disease- oriented path. The potential significance is substantial for both understanding new aspects of stem cell biology and for the development of improved drugs to prevent and/or treat common debilitating diseases such as osteoporosis, degenerative muscle diseases and diabetes. Public Health Relevance: The emergence of the field of stem cell biology has raised the real potential for regenerative medicine to offer treatments and cures for patients suffering from a broad array of illnesses including degenerative muscle diseases, osteoporosis and diabetes. The goal of this project is to test a hypothesis of how stem cell fate decisions are regulated in vivo. Elucidating the answer to this critical question in biology would facilitate the translation of the science of stem cell biology to the bedside for the development of novel therapies.